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Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C3 (C3), clusterin (CLI), haptoglobin (HP) and serum amyloid A (SAA) are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from patients with advanced breast cancer, colorectal cancer (CRC) and lung cancer compared to healthy controls (age and gender matched) using commercially available enzyme-linked immunosorbent assay kits. Logistic regression (LR) models were fitted to the resulting data, and the classification ability of the proteins was evaluated using receiver-operating characteristic curve and leave-one-out cross-validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer [area under the curve (AUC) 5 0.89, LOOCV 5 73%], CLI for CRC (AUC 5 0.98, LOOCV 5 90%), HP for small cell lung carcinoma (AUC 5 0.97, LOOCV 5 88%), C3 for lung adenocarcinoma (AUC 5 0.94, LOOCV 5 89%) and HP for squamous cell carcinoma of the lung (AUC 5 0.94, LOOCV 5 87%). The best dual combination of biomarkers using LR analysis were found to be AHSG 1 C3 (AUC 5 0.91, LOOCV 5 83%) for breast cancer, CLI 1 HP (AUC 5 0.98, LOOCV 5 92%) for CRC, C3 1 SAA (AUC 5 0.97, LOOCV 5 91%) for small cell lung carcinoma and HP 1 SAA for both adenocarcinoma (AUC 5 0.98, LOOCV 5 96%) and squamous cell carcinoma of the lung (AUC 5 0.98, LOOCV 5 84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins.

Innovations are an integral part of the evolutionary process if we accept the fact that more complex organisms derived from anatomically simple ones. All major taxa are distinguished not only by their closer genealogical relatedness relative to other species but also by the possession of novel anatomical and physiological features. The question is whether the origin of these novel characters can be simply understood as adaptations, like all other phenotypic differences that arise by natural selection, or whether the origin of these characters requires more profound genetic changes. In this paper, we argue that innovations constitute a distinct class of evolutionary processes that require a research program complementary to the study of adaptation. The distinguishing feature of innovations is the origin of novel organ identity gene functions specific to the novel character. By implication, research into the origin of novel characters has to identify the developmental regulatory links that were involved in the evolution of these characters. We suggest that novel regulatory links will include the evolution of cis-regulatory elements as well as novel protein-protein interactions among transcription factor proteins. The latter hypothesis suggests that innovations should leave a trace in the evolution of the protein coding regions of transcription factor genes. We illustrate this idea with results on the evolution of HoxA-11 and HoxA-13 in the stem lineage of placental mammals. These genes are essential for female reproductive tract development and function. We show that, as predicted, these genes experience strong directional selection in the stem lineage of placental mammals and that these amino acid substitutions affect residues at the surface of the protein, consistent with their expected role in protein-protein interactions. We conclude that a careful analysis of sequence variation in developmental genes can aid in testing which developmental changes were instrumental in the origin of novel morphological characters.

Galis and collaborators (2010) claim that our recent paper (Kohlsdorf and Wagner 2006), presenting statistical evidence for the reevolution of digits in the genus Bachia, may be flawed. Their reanalysis of the data does not support the possibility of a reevolution of digits and the authors also argue that such a reevolution would be implausible on functional and developmental grounds. In response, we reanalyzed our data with additional outgroup species. Our results differ from the one published in 2006, but this incongruence is not statistically significant. In contrast, the hypothesis presented by Galis et al. is significantly worse. An analysis of digit number evolution, using novel techniques to test for irreversibility of character loss (Goldberg and Igic 2008), confirmed our original conclusion that there is strong evidence for reevolution of digits in Bachia. We also point out that this result is not in conflict with the hypothesis by Galis and Metz (2001) that mutations affecting the initial digit patterning are associated with strong negative pleiotropic effects and thus unlikely to be fixed in evolution. An important avenue of future research will be to directly test whether reevolved digits develop from conserved digit condensations retained after digit loss.

The evolutionary significance of the female orgasm is unclear. Adaptationist accounts seek to ascribe a positive fitness benefit to females that achieve orgasm during vaginal intercourse, spawning theories that propose the female orgasm is an adaptation to bipedalism, communal life, pair-bond formation, insemination efficiency, and mate quality assessment, among others (reviewed in Lloyd 2005). Structuralist accounts explain female orgasm as a byproduct of the evolutionary, developmental, and physiological processes that generate the male orgasm (Lloyd 2005). Thus, the byproduct hypothesis asserts that the female orgasm results from shared evolutionary and developmental processes with males and is not the result of direct selection on the trait in females. The primary evidence cited in favor of the byproduct hypothesis is the high variability in womens’ ability to achieve orgasm during vaginal intercourse compared with the near certainty of male orgasm (Lloyd 2005). A prediction of this hypothesis is that a lack of selection on female orgasm releases the genital structures responsible for triggering orgasm in women (the clitoris) from selection, leading to greater phenotypic variation than for structures under stronger selection pressure for achieving an orgasm (i.e., the penis) (Wallen and Lloyd 2008). Wallen and Lloyd (2008) recently used this expectation to examine the variability in clitoral and penile lengths for evidence of differential selection pressure. Comparing the coefficient of variation in length between the clitoris and penis from large datasets (Table 1), Wallen and Lloyd (2008) found that clitoral length was significantly more variable than penile length (P50.002). These authors concluded, ‘‘given the close connection between the clitoral structures and womens’ orgasms, this marked variability in clitoral [length, compared with variability in penile length,] suggests little or no selective pressure on clitoral structures’’ (Wallen and Lloyd 2008). However, this conclusion rests on two important assumptions: (1) clitoral length is directly related to a womens’ ability to achieve orgasm, and (2) length is the best metric for the size of the penis and clitoris. Available data refute the former assumption, while the latter is clearly a one-dimensional view of size that may not be an accurate measure of ‘‘size.’’ A more realistic metric for size should include a description of both length and width, such as volume. Therefore, I performed the same analysis as Wallen and Lloyd (2008), but used volume measures instead of length. Unlike the results reported by Wallen and Lloyd (2008) for length data, clitoral volume was not significantly different from penile volume (1.39-fold difference, P50.17; Table 1). Following the rationale of Wallen and Lloyd (2008), volume data suggest that the size of the clitoris and penis are under similar selection pressures, in contrast to their conclusion for length data. This result is particularly surprising given the strong signature of co-evolution between penile and vaginal length reported by Wallen and Lloyd (2008), which suggests that clitoral size (as measured by volume) is under particularly strong stabilizing selection despite variability in length among women. More generally, the primary argument used to support the byproduct hypothesis for the origin of the female orgasm is its uncertain occurrence during sex, which is taken as evidence for reduced or absent stabilizing selection on female orgasm. Thus, Wallen and Lloyd (2008) assume that the clitoris, as the structure primarily responsible for generating the orgasm (Narjani 1924; Masters and Johnson 1966), must also be free from stabilizing selection and this will be reflected in variation in its size. This relationship is essential for their conclusions, however, there is no relationship between clitoral size and ability to achieve orgasm (Masters and Johnson 1966). For that matter, it seems unlikely that penis size is directly related to a male’s ability to reach orgasm during sex. Indeed, the ape penis is much smaller than the human penis with the average chimpanzee’s penis approximately 14-cm long, and the average gorilla and orangutan penis only approximately 3-cm long (Diamond 1992). Yet I doubt proponents of the byproduct hypothesis would conclude that males of these species experience orgasm during intercourse less frequently than human males. Attempts to explain the female orgasm have provoked a growing and sometimes heated debate (Barash 2005; Judson 2005; Zuk 2006; see Amundson 2007 for a thoughtful review). Yet, empirical data to test hypotheses, both functional and EVOLUTION & DEVELOPMENT 10:4, 396 –397 (2008)